Significant association between asthma and a lower risk of mortality among COVID-19 patients in Spain: A meta-analysis

Background Various prevalences of asthma in coronavirus disease 2019 (COVID-19) have been reported in different regions, and the association between asthma and COVID-19 subsequent mortality has been in debate. Thus, this study aimed to investigate whether there was a significant association between asthma and COVID-19 mortality in Spain through a meta-analysis. Methods The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were strictly complied with conducting this study. The pooled odds ratio (OR) with a corresponding 95% confidence interval (CI) was calculated by a random-effects model. The I2 statistics for heterogeneity, sensitivity analysis for robustness, Begg’s test, and Egger’s test for publication bias, along with subgroup analyses for confounding bias, were also performed to support the foundation of this study. Results The meta-analysis revealed that asthma was significantly associated with a lower risk of mortality among COVID-19 patients in Spain with a random-effects model (pooled OR = 0.78, 95% CI = 0.69–0.88, I2 = 35%). Further subgroup analyses by male proportion and sample size also indicated that a statistically significant negative correlation did exist between asthma and COVID-19 mortality. Robustness and no publication on-bias were evidenced by sensitivity analysis, Egger’s test, and Begg’s test, respectively. Conclusion In conclusion, patients with asthma were found to have a lower risk of mortality from COVID-19 in Spain, especially among elderly patients. In addition, asthmatic patients infected with COVID-19 may be at risk of death compared to non-asthmatic patients, which is not a cause for undue concern, thereby reducing the burden of medication.


INTRODUCTION
The novel coronavirus disease 2019 (COVID- 19), caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection, has led to over seven million fatalities in infected patients globally as of February 2024, with symptoms of the infection varying widely from asymptomatic to presenting as fatal acute respiratory distress syndrome. 1The widespread COVID-19 epidemic poses a serious threat to life and health, especially for older people, males, and people with underlying comorbidities, and the World Health Organization officially announced on May 5, 2023, that COVID-19 no longer constituted a public health emergency of international concern and that surveillance had shifted from emergency response to long-term disease prevention, control, and management. 2,3The available evidence suggests that COVID-19 vaccination is the dominant strategy against severe outcomes and mortality of COVID-19, 4 while asthmatic patients were considered a higher risk group for severe bronchospasm after COVID-19 vaccine injection. 5hen asthma was also identified as an independent variable that was significantly associated with low vaccination rates. 6Additionally, the Barcelona study showed that asthmatic patients were not susceptible to the SARS-CoV-2 virus, on the contrary, patients with T2 asthma were even immune to the virus to a high degree. 7he current debate on COVID-19 has centered on differences between countries, while European countries have adopted different times and methods for self-isolation.As one of the most common noncommunicable diseases across Spain, asthma continues to face major diagnostic challenges in adults, such as over-and underdiagnosis. 8In Spain, the average prevalence of asthma in adults is 5%, and in children, it is twice as high, while uncontrolled asthma is mostly Significant association between asthma and a lower risk of mortality among COVID-19 patients in Spain overall research.When publications with data derived from the same period and location were found, only the articles with a larger sample size or a more complete analysis were included in the study.

Article eligibility criteria
After removing duplicates, two separate investigators evaluated the inclusion eligibility of studies by assessing the titles, abstracts, and full texts.Studies were included in the meta-analysis if the following criteria could be met: (1) all patients were confirmed with COVID-19 infection in Spain; (2) peer-reviewed articles published in English; and (3) articles clearly reported the number of alive and dead with comorbid asthma or not in COVID-19 patients, or the effect size with a 95% confidence interval (CI) regarding the relation between asthma and COVID-19 mortality.Preprints, reviews, case reports, errata, and studies without available data were excluded.

Data extraction and analysis
The following main information was extracted in order: first author, sample size, the mean (standard deviation) or median (interquartile range) age, proportion of males, available data on the incidence of the alive and the dead among COVID-19 patients or the effect size with 95% CI, and setting from each study.The process was carried out by the two independent investigators.Once divergences happened, the next negotiating situation would come into effect, and the third person made the final decision.
The pooled odds ratio (OR) and 95% CI were calculated by a random-effects model using R software (version 4.2.2).Heterogeneity among individual studies was evaluated using the I 2 statistic. 15Sensitivity analysis, omitting each article, was applied to examine the stability of our results.Publication bias was valued through Begg's rank correlation test and Egger's linear regression test. 16,17The standard of statistical significance was defined as a two-tailed p value <0.05.

Study selection and study characteristics
The PRISMA flow diagram shown in Figure 1 depicts our search methodology.The online literature search provided 976 articles from Significant association between asthma and a lower risk of mortality among COVID-19 patients in Spain electronic databases.Twenty references of the included studies or reviews were retrieved via hand-searching to obtain as many relevant studies as possible.After screening all abstracts/titles, 920 full-text articles were excluded.A further 38 studies were excluded after a detailed assessment of the number of the alive and the dead with comorbid asthma or the effect size with a 95% CI according to inclusion and exclusion criteria. All studies were related to Spain, with sample sizes ranging from 57 to 86,867 patients based on the clear endpoint of death.Thirty-one studies were based on hospitalized patients, and the remaining seven studies were based on all patients and addressed the relationship between asthma and COVID-19 mortality.The age of the patients included in the eligible studies ranged from 36.9 to 75.9 years.In most studies, more than half of the participants were male.Of interest, the prevalence of asthma in COVID-19 patients varied from 2 to 12.8% among the included studies.The primary characteristics of eligible studies are presented in Table 1.

Sensitivity analysis and publication bias
As shown in Figure 3, the forest plot indicated that the pooled OR did not change significantly by the singular exclusion of the included studies, which indicated the robustness of this study.The p-values for the Begg test (Figure 4A) and the Egger test (Figure 4B) were 0.870 and 0.642, respectively, and these results did not provide evidence of a significant effect of publication bias.

DISCUSSION
Understanding the risk variables is critical to selecting those who should be vaccinated first.4][55] It is not widely known whether asthma additionally serves as an aggravating factor for worsening COVID-19 outcomes.To our knowledge, this is the first quantitative meta-analysis to investigate the impact of asthma on the risk of COVID-19 mortality in Spain.The data based on 38 studies involving 260,351 COVID-19 patients indicated that asthma was a significant protective factor for COVID-19 death in Spain.Further subgroup analyses by male proportion and sample size also indicated that COVID-19-infected patients with asthma had a lower risk of dying, especially among older patients.The lower heterogeneity of the included studies indicated the reliability of the results and also excluded, to some extent, the interference of the diversity of COVID-19 prevention and control measures in different regions.Despite the under-and over-diagnosis of asthma in Spain, as mentioned in the introduction, our study suggested that asthma was a protective factor from COVID-19-induced death, especially during the pandemic.This seems like a good surprise for the routine control of asthma.The main focus of Significant association between asthma and a lower risk of mortality among COVID-19 patients in Spain The age (years) was presented as mean ± standard deviation or median (interquartile range, IQR).CI: confidence interval, NR: not clearly reported.

Table 1.(Continued)
Significant association between asthma and a lower risk of mortality among COVID-19 patients in Spain  Significant association between asthma and a lower risk of mortality among COVID-19 patients in Spain obstruction.Asthmatic patients have been reported to experience significant bronchospasm within 10-20 minutes after the first dose of the mRNA COVID-19 vaccine. 61However, there was sporadic evidence suggested that adverse reactions such as acute bronchospasm were rare in patients with severe asthma after the COVID-19 vaccination. 62dditionally, studies involving larger sample sizes have shown that vaccines were effective in preventing hospitalization for COVID-19 and respiratory failure complicating COVID-19 among patients with chronic respiratory diseases (including asthma). 63Further research to elucidate the safety of the COVID-19 vaccination for asthmatic populations is needed.A recent study found lower rates of COVID-19 vaccination among young people from families with lower socioeconomic status and with asthma, including those with uncontrolled asthma. 64Bossios et al. investigated the experience of COVID-19 vaccination in patients with severe asthma and found that vaccination had little effect on asthma control. 65In contrast, another study showed that asthmatic patients treated with biologic therapies such as benralizumab (IL-5 receptor antagonist) or mepolizumab (IL-5 antagonist) had a reduced asthma management is on the routine control of asthma symptoms, reducing the risk of worsening symptoms and hospitalization, and at the same time minimizing the adverse effects of medications, especially inhaled corticosteroids.Corticosteroids were also used to prevent and control disease progression during the SARS (severe acute respiratory syndrome coronavirus) epidemic and the early stages of the COVID-19 infection.This may partly explain our results and also provide some suggestions for the management of asthma during the pandemic.
The COVID-19 vaccines provide strong protection against severe illness and death. 56,57Although it is still possible to get COVID-19 after vaccination, they are more likely to have mild or no symptoms. 58dentifying populations contraindicated to vaccination and those at high risk of poor prognosis is the major area of concern beyond COVID-19.The rate of allergic reactions to the COVID-19 mRNA vaccine is higher in patients with a history of high-risk allergies. 59,60As we know, allergic asthma is the most common type of asthma and is accompanied by eosinophilic airway inflammation, massive mucus production, airway hyper-responsiveness, and reversible airway Significant association between asthma and a lower risk of mortality among COVID-19 patients in Spain The pathophysiology of asthma concentrates on two primary immunologic pathways; both endotypes are usually categorized as airway eosinophilia and type-2-inflammation. 74,75 Of these, peripheral blood eosinophil counts served as markers to identify endotypes and for asthma treatment, and eosinophils may also promote protective responses against respiratory viruses. 76,77n such a situation, possible molecular mechanisms of SARS-CoV-2 infection causing death with asthma seemed to be explained in recent studies.Angiotensin-converting enzyme 2 (ACE2) could act as a cellular receptor for SARS-CoV-2, just like SARS-CoV.Higher ACE2 gene expression was found to be positively associated with COVID-19, both in terms of susceptibility 78 and severity of COVID-19. 79However, reducing ACE2 expression was found in respiratory allergies and controlled allergen exposures, including allergic sensitization and asthma. 802][83][84][85] The expression of ACE2 and TMPRSS2 was lower in the respiratory epithelial cells of asthma patients taking inhaled corticosteroids. 86orticosteroids, which are routinely used to treat asthma, affect the expression of the ACE2 or TMPRSS2 gene in sputum cells, and other drugs for asthma might decrease inflammation and enhance antiviral defense. 87,88In addition, individuals with asthma were considered to be at higher risk of unfavorable clinical outcomes from COVID-19 in the early phase of the pandemic, which made COVID-19 patients with asthma receive more medical care and preferential treatments.The above explanations might shed some light on the relationship between asthma and the lowered risk of COVID-19-related death.Further evidence focusing on the underlying molecular mechanisms is required to validate the observed association.Several limitations inevitably existed in this metaanalysis.First, the pooled OR was estimated on the unadjusted effect sizes, which meant the role of confounding factors might be overlooked.Therefore, risk factor-adjusted estimates would be necessary to verify the current findings.Second, as a sort of chronic disease, asthma type, severity, vaccination status, and routine medications might account for the correlation COVID-19 vaccine response. 66Although more than 86% of the Spanish population is currently vaccinated with full doses, only about 2% of Spaniards who are eligible for the COVID-19 vaccine have refused it, including those who could not be vaccinated for medical reasons. 67However, there are few available data on COVID-19 vaccination for asthmatic patients in Spain.
On the one hand, the incidence of respiratory disease caused by rhinoviruses and viral loads is higher in asthmatic patients compared to healthy subjects.Once asthma was out of effective control, the severity of virus-induced deterioration worsened dramatically. 68Additionally, when asthmatic children presented to the emergency department with COVID-19, they were more likely to develop severe disease than patients without asthma. 69Conversely, on the other hand, there was also evidence that asthma did not impact negatively but rather positively on the outcomes of COVID-19. 70,71This was consistent with our findings, especially among elderly patients.
Although previous studies have shown that old age is a risk factor for COVID-19 infection and asthma, even with a poor prognosis. 55However, in our study, a phenomenon worthy of attention is that ≥60-year-old asthmatic patients had a relatively lower risk of death in COVID-19 compared to the <60-year-old group (0.73 vs. 0.97).Despite the fact that the exact reasons for the potentially protective effect of asthma on COVID-19 death in elderly patients in our study are not known, we hypothesize that this may be partly attributable to the following reasons.In part, it is due to the fact that there are nearly 10 million Spanish citizens over the age of 65 years with a high life expectancy and that the vaccination strategy in Spain during the pandemic was age-segmented, 72 progressively moving from the older to the younger age groups, with a 90% vaccine coverage in the over 60-yearold age group but a lower percentage of vaccinations in younger age groups.The other is partly attributable to the clinically intensive treatment of COVID-19 elderly patients with asthma.Asthma constituted the majority of the disability-adjusted life years index, with the highest incidence rate in the young group. 73This suggests a putative mechanism by which asthma may be responsible for death from the COVID-19 infection.
Significant association between asthma and a lower risk of mortality among COVID-19 patients in Spain Wang, and Li Shi (all from the Department of Epidemiology, School of Public Health, Zhengzhou University) for their kind help in searching articles, collecting data, and valuable suggestions for data analysis.

Figure 2 .
Figure 2. Forest plot for the relationship between asthma and the risk of mortality among coronavirus disease 2019 (COVID-19) patients with pooled odds ratio (OR) and 95% confidence interval (CI).

Figure 3 .
Figure 3. Sensitivity analysis for pooled OR and 95% CI by omitting one study at a time.

Figure 4 .
Figure 4. Plots of publication on-bias: (A) based on Begg's test and (B) based on Egger's test.

Table 1 . General information of the eligible studies included in this meta-analysis.
Significant association between asthma and a lower risk of mortality among COVID-19 patients in Spain This study was supported by grants from the National Natural Science Foundation of China (No. 81973105), the Key Scientific Research Project of Henan Institution of Higher Education (No. 21A330008), the Joint Construction Project of Henan Medical Science and Technology Research Plan (No. LHGJ20190679), and the Henan Young and Middle-aged Health Science and Technology Innovation Talent Project (No. YXKC2021005).The funders have no role in the data collection, data analysis, preparation of the manuscript, and decision to submission.Significant association between asthma and a lower risk of mortality among COVID-19 patients in Spain VOL. 2024 / ART.34 CI: confidence interval, HR: hazard ratio, OR: odd ratio, RR: risk ratio, USA: the United States of America.